Pitfalls in Diagnosing Neuraminidase Deficiency: Psychosomatics and Normal Sialic Acid Excretion

Abstract

Neuraminidase deficiency (mucolipidosis I, sialidosis types I and II, cherry-red spot myoclonus syndrome) is a lysosomal storage disorder with an expanding clinical phenotype. Here, we report the striking diagnostic history of late-onset neuraminidase deficiency in two sisters, currently aged 14 (patient 1) and 15 (patient 2).

Patient 1 was referred for evaluation of her vision after a traffic accident. During this examination, nummular cataract, macular cherry-red spot, and optic nerve atrophy were seen. Furthermore, tremors were noticed in her arms and legs. This combination suggested a lysosomal storage disorder. Her family history revealed an older sister, patient 2, who had a long history of unexplained neurologic symptoms; she was under unsuccessful treatment for conversion disorder. Patient 2 showed identical ophthalmological findings. In retrospect, she had presented with avascular osteonecrosis of the right femur head at age 9.

Urinary oligosaccharide patterns and enzyme activity revealed neuraminidase deficiency in both patients. Urinary-bound sialic acid levels were normal. Sequencing of NEU1 demonstrated two known compound heterozygous mutations (c.1195_1200dup p.His399_Tyr400dup; c.679G>A, p.Glu227Arg).

The substantial time window between onset of typical symptoms and diagnosis in patient 2 suggests inadequate awareness of lysosomal storage disorders among clinicians. Of special interest is the observation that normal urinary sialic acid levels do not exclude neuraminidase deficiency. Urinary oligosaccharide screening is essential to diagnosis in such cases. In addition, patient 2 is the fourth case in the literature with a history of femur head necrosis. Bone defects might therefore be an early manifestation of late-onset neuraminidase deficiency.

Competing interests: None declared

Appendices

Synopsis

Diagnosis of neuraminidase deficiency in two sisters, first misdiagnosed with conversion disorder, shows importance of urinary oligosaccharide screening when sialic acid excretion is normal and suggests osteonecrosis as an early symptom.

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Conflict of Interest

Imre Schene, Viera Ayuso, Koen van Gassen, Monique de Sain- van der Velden, Inge Cuppen, Peter M. van Hasselt, and Gepke Visser declare that they have no conflict of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.

Details of the Contributions of Individual Authors

Imre Schene drafted the first manuscript.

Viera Kalinina Ayuso is the ophthalmologist who executed the ophthalmological examinations, contributed Fig. 1, and revised the manuscript.

Koen van Gassen executed the genetic investigation that demonstrated the compound heterozygous mutations in NEU1 and revised the manuscript.

Monique de Sain- van der Velden executed the metabolic investigations, contributed Fig. 3 and revised the manuscript.

Inge Cuppen is the pediatric neurologist who executed the neurological examination in our center and revised the manuscript.

Peter M. van Hasselt contributed to the follow-up of the patients and revised the manuscript.

Gepke Visser is the metabolic pediatrician of the patients and coordinated and revised the manuscript.